This program is focused upon ocular surface immune-mediated diseases and has emphasized dry eye, which affects 4.3 million Americans over the age of 65 with symptoms often or all of the time. This segment of the US population that will nearly double in 25 years. The current treatment of dry eye is palliative only and Americans spend over $100 million per year for lubricating eye drops. We recently completed a masked trial of Cyclosporine eye drops for the treatment of dry eye. We found elevated and comparable conjunctival inflammatory cell sub-populations and markers of immune activation in patients with both Sjogrens' Syndrome, a systemic autoimmune disease, and in the common form of dry eye. This is tangible evidence of an inflammatory basis for dry eye and confirms the rationale of anti-inflammatory therapy for its treatment. Compared to the vehicle alone, a significanly higher proportion of patients treated with Cyclosporine showed improvement in 3 out of 5 primary objective measures including: ocular surface staining, basal tear production and visual acuity. We are also investigating the treatment of Sjogren's Syndrome, a particularly severe form of dry eye, in collaboration with the NIDCR in 2 masked, placebo-controlled trials of DHEA and Etanercept treatment. The DHEA trial has recently been completed and data analysis is underway. The Etanercept trial is ongoing. We have identified women with Premature Ovarian Failure as a new population of patients at risk for the development of dry eye. Compared to age-matched women, significantly more patients with Premature Ovarian Failure use ocular lubricants and have signs and symptoms of dry eye. These patients scored significantly worse than controls on all 3 symptom questionnaires used and showed significantly more eye damage measured by ocular surface vital dye staining using validated grading schemes. These findings suggest that the dysregulation of hormones and immunologic dysfunction seen in Premature Ovarian Failure may play a role in the pathogenesis of ocular surface disease in these patients. We have also developed a non-invasive technique which can replace a surgical biopsy under anesthesia for the diagnosis of Mucolipidosis Type IV, a disease which causes neurologic and ocular abnormalities, vision loss and mental retardation in children. We have completed a study examining the natural history of the ocular manifestations of this disease, developed a standardized grading scheme to assess the severity of the eye findings and are the first to show that the visual and eye problems of these patients get worse over the age of 10 years, in contrast to their neurologic status, which tends to remain stable. Our work could change the way children with Mucolipidosis Type IV are diagnosed and alter the occupational therapy they receive. The defective protein and gene for this disease have recently been identified, (MCOLN1). It will be critical to employ objective outcome measures, such as those we have developed, when a potential treatment is identified and tested.